International Agency for Research on Cancer (IARC) - Summaries & Evaluations

ACRYLAMIDE
(Group 2A)

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Acrylamide has been produced since the 1950s by hydration of acrylonitrile.
It is used mainly to produce water-soluble polyacrylamides used
as flocculents for clarifying drinking-water, for treating municipal
and industrial waste waters and as flow control agents in oil-well
operations. Other major uses of acrylamide are in soil stabilization,
in grout for repairing sewers and in acrylamide gels used in biotechnology
laboratories. The major routes of exposure at the workplace appear
to be dermal absorption of acrylamide monomer from solution and
inhalation of dry monomer or aerosols of acrylamide solution.
Exposure occurs during acrylamide and polyacrylamide manufacture,
during acrylamide grouting and during laboratory preparation of
polyacrylamide gels.

5.2 Human carcinogenicity data

Two cohort mortality studies were conducted among workers exposed
to acrylamide. The first showed no significant excess of cancer
but suffered from small size, short duration of exposure and short
latency. In the other study, in one Dutch and three US plants,
a nonsignificant increase was seen in deaths from pancreatic cancer,
but there was no trend with increasing exposure.

5.3 Animal carcinogenicity data

Acrylamide was tested for carcinogenicity in one experiment in
rats by oral administration. It increased the incidences of peritoneal
mesotheliomas found in the region of the testis and of follicular
adenomas of the thyroid in males and of thyroid follicular tumours,
mammary tumours, glial tumours of the central nervous system,
oral cavity papillomas, uterine adenocarcinomas and clitoral gland
adenomas in females. In screening bioassays, acrylamide, given
either orally or intraperitoneally, increased both the incidence
and multiplicity of lung tumours in strain A mice.

Acrylamide was also tested as an initiating agent for skin carcinogenesis
after oral, intraperitoneal and topical administration to mice
of one strain and after oral administration to mice of another
strain, followed by topical treatment with 12-O-tetradecanoylphorbol
13-acetate. It induced a dose-related increase in the incidence
of squamous-cell papillomas and carcinomas of the skin in all
four experiments.

5.4 Other relevant data

In occupational settings, acrylamide is taken up both through
the skin and by inhalation. Damage to both the central and peripheral
nervous systems has been reported on several occasions in exposed
humans and has been thoroughly studied in animals.

Acrylamide is metabolized in vitro and in vivo in mice, rats and
humans to the epoxide, glycidamide. Both substances are equally
distributed throughout the tissues and have half-lives of about
5 h in rats; acrylamide itself has also been shown to be uniformly
distributed between tissues in several other species. The conversion
of acrylamide to glycidamide is saturable, ranging from 50% at
very low doses to 13% at 100 mg/kg bw in treated rats. Both agents
are detoxified by glutathione conjugation, and glycidamide is
also detoxified by hydrolysis. Both agents react directly with
haemoglobin in vivo, but DNA adducts result only from the formation
of glycidamide.

The presence of haemoglobin adducts of acrylamide was correlated
with neurotoxicity in a group of highly exposed workers.

Acrylamide was not teratogenic to rats or mice after oral treatment
of dams with doses up to the toxic level. It causes testicular
atrophy, with damage to spermatids and mature spermatozoa. Reduced
sperm motility, impaired fertility and dominant lethal mutations
at the spermatozoa stage have also been reported in mice and rats.
A single study in rats provides evidence that the testicular damage
is not secondary to neurotoxicity, since testicular damage but
not neurotoxicity was induced by injection of the reactive epoxide,
glycidamide.

The genotoxicity of acrylamide has been studied extensively. It
induces gene mutation, structural chromosomal aberrations, sister
chromatid exchange and mitotic disturbances in mammalian cells
in vitro in the presence or absence of exogenous metabolic systems.
It induces structural chromosomal aberrations in vivo in both
somatic and germ-line cells. Chromosomal aberrations and micronuclei
were induced in mouse bone marrow and in premeiotic and postmeiotic
cells. Treatment with acrylamide in vivo also caused somatic mutation
in the spot test, heritable translocation and specific locus mutations
in mice and dominant lethal mutations in both mice and rats in
several studies. Acrylamide induces unscheduled DNA synthesis
in rat spermatocytes in vivo but apparently not in rat hepatocytes;
glycidamide induced unscheduled DNA synthesis in rat hepatocytes
in one study in vitro. Acrylamide induces transformation in cultured
mammalian cells. It does not induce mutation in bacteria, but
glycidamide does in the absence of an exogenous metabolic system.
Acrylamide induces sex-linked recessive lethal and somatic mutations
in Drosophila.

5.5 Evaluation

There is inadequate evidence in humans for the carcinogenicity
of acrylamide.

There is sufficient evidence in experimental animals for
the carcinogenicity of acrylamide.

In making the overall evaluation, the Working Group took into
consideration the following supporting evidence:

(i) Acrylamide and its metabolite glycidamide form covalent adducts
with DNA in mice and rats.

(ii) Acrylamide and glycidamide form covalent adducts with haemoglobin
in exposed humans and rats.

(iii) Acrylamide induces gene mutations and chromosomal aberrations
in germ cells of mice and chromosomal aberrations in germ cells of rats
and forms covalent adducts with protamines in germ cells of mice
in vivo.